tbuckley/cabot-search huggingface dataset:
Abstract 376: DKK1 inhibition can overcome sorafenib resistance in hepatocellular carcinoma cells through beta-catenin suppression
Authors: Lin Li, Chia-Lang Hsu, Liang-In Lin, Bin-Shyun Lee, Ping-Yun Ou, Ann-Lii Cheng, Chiun Hsu, Da-Liang Ou
Journal: Cancer Research (2023)

Abstract As part of our previous studies on the anti-tumor mechanisms of sorafenib, one of the primary treatments for advanced hepatocellular carcinoma (HCC), we found that suppression of cyclin E1 in HCC cells correlates with sensitivity to sorafenib (Chiun Hsu et al. Clin Cancer Res. 2016:2555). Furthermore, the combination of sorafenib and a cyclin-dependent kinase inhibitor was found to have synergistic anti-tumor effects. Specifically, we found that inhibiting DKK1 (dickkopf1), an essential regulator of Wnt signaling, had a synergistic effect. In sorafenib-sensitive HCC cells, DKK1 mRNA and protein expressions were suppressed following treatment with sorafenib, but not in sorafenib-resistant cells. HCC cells resistant to sorafenib were induced to apoptosis with knockdown of DKK1 expression. The apoptosis-inducing effects of sorafenib were enhanced by DKK1 inhibitors, and beta-catenin suppression was found to be crucial to this effect. In addition, mouse tumors secrete DKK1 into the blood and its presence correlates positively with tumor size and survival during sorafenib treatment. Suppression of DKK1 in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib or CDK inhibitor efficacy. Sorafenib combined with a DKK1 inhibitor may improve sorafenib's efficacy in hepatocellular carcinoma. (Supported by MOST 106-2314-B-002-229-MY3, MOST 109-2634-F-002-043, MOST 109-2314-B-002-229 -MY3, MOST 110-2634-F-002-044 from Ministry of Science and Technology, Taiwan) Citation Format: Lin Li, Chia-Lang Hsu, Liang-In Lin, Bin-Shyun Lee, Ping-Yun Ou, Ann-Lii Cheng, Chiun Hsu, Da-Liang Ou. DKK1 inhibition can overcome sorafenib resistance in hepatocellular carcinoma cells through beta-catenin suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 376.
Abstract 3757: miR-200 inhibits the activation of cancer-associated fibroblasts in lung tumor microenvironment
Authors: Inyoung Cheon, Sieun Lee
Journal: Cancer Research (2023)

Abstract Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and promote cancer progression and metastasis. CAFs are regulated by diverse processes including regulation by miRNAs. To identify miRNAs involved in the regulation of CAF activation, we profiled miRNA expression within mouse lung normal fibroblasts (LFs) and CAFs using the NanoString nCounter method. Among numerous miRNAs differentially expressed between CAFs and LFs, miR-200 was selected for further investigation, which is more highly downregulated in CAFs. Overexpression of miR-200 in CAFs suppressed the migration and invasion of lung cancer cells in co-culture systems and inhibited metastasis in a mouse model. In addition, we verified that lung cancer patients with high miR-200 levels showed a good prognosis than those with low miR-200 levels. Next, we tried to identify novel miR-200 targets based on RNA sequencing data, lung adenocarcinoma TCGA, and TargetScan. NRP2 was confirmed to be a target of miR-200 by 3΄-UTR assay. NRP2 knockdown by siRNAs in CAFs suppressed cancer cell invasion, and NRP2 addback in CAF-200 restored cancer cell invasion inhibited by miR-200. NRP2 functions as a co-receptor with VEGFR, thus, CAF-200 was less responsive to VEGF than control CAFs. Collectively, this study suggests that downregulation of miR-200 in CAFs promotes lung cancer progression in tumor microenvironment; therefore, miR-200 will be a good therapeutic target or a biomarker in lung adenocarcinoma. Citation Format: Inyoung Cheon, Sieun Lee. miR-200 inhibits the activation of cancer-associated fibroblasts in lung tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3757.
Abstract 1599: Targeting tumor synthetic vulnerabilities and immune evasion mechanisms with CO-1002
Authors: Daniel Ciznadija, Gemechis Degaga, Abdul Mondal, Maxwell Hillbert, Cong Chen, Bikash Debnath, Sonam Mehrotra, Brandon Jones, Ralph Rivero, Kakajan Komurov
Journal: Cancer Research (2023)

Abstract Cancer immunotherapy with immune checkpoint inhibitors (ICI) has shown durable clinical benefits in patients with immune-hot tumors. However, the majority of cancers are characterized by an immune-cold tumor microenvironment, which are refractory to ICI therapy. Targeting of tumor synthetic vulnerabilities due to genomic alterations is another promising approach that has proven effective in the clinic (e.g. PARP inhibitors in BRCA-mutant tumors). Here, we aimed to identify therapeutic targets that have dual liabilities in tumor cell survival and the evasion of anti-tumor innate immune responses. Applying machine learning approaches to a manually curated compendium of public and proprietary datasets, we identified and validated several genes with a high potential of conferring tumor-intrinsic cell survival and blocking of innate pro-inflammatory responses in immune-cold tumors. The targeting of these genes induced robust cell killing and activation of innate immune response pathways in specific molecularly-defined tumor populations, including immune-cold cells. A series of highly potent small molecule compounds were established against these targets using structure-based design, which shows robust in vitro and in vivo target engagement and favorable cytotoxic and phenotypic profiles across a large panel of cancer cell lines and PDXs. Collectively, this therapeutic program shows significant promise in treating a multitude of solid tumors as a monotherapy and in combination with currently approved immune therapies. Citation Format: Daniel Ciznadija, Gemechis Degaga, Abdul Mondal, Maxwell Hillbert, Cong Chen, Bikash Debnath, Sonam Mehrotra, Brandon Jones, Ralph Rivero, Kakajan Komurov. Targeting tumor synthetic vulnerabilities and immune evasion mechanisms with CO-1002 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1599.
Abstract 1016: Prognostic factors for overall survival, recurrence-free survival, and metastasis-free survival of colon cancer in Morocco
Authors: Fatima El Agy, Laila Chbani
Journal: Cancer Research (2023)

Abstract Introduction: Colon cancer is the third most common cancer in Morocco. Its incidence and mortality rate is constantly increasing in this country. This requires the determination of clinical and molecular prognostic factors of CC in our context. Studies indicate that mutations in the RAS genes (KRAS and NRAS) represent such a factor. The aim of this study is to evaluate the prognostic impact of KRAS and NRAS mutations on overall survival (OS), recurrence-free survival (RFS) and metastasis-free survival (MFS) of CC patients. Methods This study involved a series of 210 patients with colon cancer. The clinical and pathological data were obtained from of each patient’s files at the molecular pathology department of the CHU HASSAN II of FES. For molecular data, full RAS status was determined by direct sequencing and Q24 pyrosequencing, after extraction of DNA from formalin-fixed and paraffin-embedded tissue. The evaluation of the relationship between OS, RFS, and MFS and the molecular and clinical factors of the patients was performed by the Kaplan-Meier method and the log-rank test. Results The average age of our patients was 57.5 ± 14.6 years. A slight male predominance was found (52.7%). 39.5% of the cases had a mutation in one of the RAS genes. Mutation of exon 2 of the KRAS gene was the most frequent with a percentage of 36.6%. The NRAS gene was mutated in 2.8% of our patients. The exon 2 mutated tumors were significantly associated with female gender (p=0.04), and left location (p=0.04) compared to the other exons. The mean OS, RFS, and MFS were 100.0%, 92.0% and 92.1% respectively. OS was significantly longer in tumors with KRAS exon 4 mutations compared to tumors with other types of RAS mutations and was also associated with right colon tumors (P=0.001), localized stages I-II (P=0.001), tumors without metastatic nodes (P=0.03), and MSI tumors (P=0.01). For RFS and MFS, localized stage and tumors without metastatic nodes were good prognostic factors (p=0.002, p=0.000). However, the type of mutated exon had no prognostic impact on either. Conclusion In our setting right location, localized stage, absence of metastatic nodes, MSI status and mutated status of exon 4 of the KRAS gene (compared to other exons) are all predictive factors of better overall survival of colon cancer in Morocco. The type of the mutated exon of the RAS genes has no impact on RFS and MFS. Citation Format: Fatima El Agy, Laila Chbani. Prognostic factors for overall survival, recurrence-free survival, and metastasis-free survival of colon cancer in Morocco [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1016.
Abstract 5613: Tumor glucose metabolism profiles detected via [18F]-FDG PET/CT correlate with the immune landascape in soft-tissue sarcomas
Authors: Amandine Crombe, Frédéric Bertolo, Jean-Philippe Guegan, Alban Bessede, Raul Perret, Mariella Spalato-Ceruso, Maud Toulmonde, Audrey Laroche, Francois Le Loarer, Vanessa Chaire, Michèle Kind, Carlo Lucchesi, Antoine Italiano
Journal: Cancer Research (2023)

Abstract Background: Improving the assessment of the immune landscape of soft-tissue sarcoma (STS) through imaging biomarkers could help better selecting and monitoring patients that could benefit from immunotherapy. Our aim was identify whether metabolic patterns of soft-tissue sarcoma (STS) on pre-treatment 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET/CT) were associated with different immune profiles on molecular and cellular levels. Methods: This single-center prospective study included consecutive adult patients with newly-diagnosed, non-metastatic, high-grade STS treated in a curative intent with available pre-treatement 18F-FDG-PET/CT. Maximal standardized uptake value (SUVmax), SUVpeak, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were extracted. A cross-validated principal component analysis (PCA) was developed on the PET/CT metrics. The first two principal components (PC1 and PC2) and an unsupervised metabolic classifications were computed. Differential gene expression (DGE), oncogenesis pathways analyses, complexity index in sarcoma (CINSARC) molecular signature and immunohistochemistry panels (CD8, CD14, CD20, CD45, CD68, c-MAF) were performed. Correlations between nuclear imaging, immunohistochemistry and transcriptomics data were achieved. Results: 85 patients were included (median age: 62 years, 37 women) between 2016 and 2021. The robust PCA defined 3 metabolic groups (high [n=21], intermediate [n=15] and low [n=49]). PC1 reflected the tumor metabolism and PC2 the size and amount of necrosis. Transcriptomics and immunohistochemistry data were available in 32 and 31 patients, respectively. PC1 was significantly positively correlated with CINSARC (P=0.0029) and the cellular densities in CD8+, CD14+, CD45+, CD68+ and c-MAF (range of P-values: 0.0175-0.0499). The metabolic-high group was characterized by the upregulation of 13 immune pathways, including ICOS, CD27, IFNG, CXCL9-10/CXCL3 genes. Conclusion: Metabolic profiles on 18F-FDG-PET/CT of high-grade STS highlights distinct immune profiles, which could pave the way for potential biomarkers of STS immunophenotyping. Citation Format: Amandine Crombe, Frédéric Bertolo, Jean-Philippe Guegan, Alban Bessede, Raul Perret, Mariella Spalato-Ceruso, Maud Toulmonde, Audrey Laroche, Francois Le Loarer, Vanessa Chaire, Michèle Kind, Carlo Lucchesi, Antoine Italiano. Tumor glucose metabolism profiles detected via [18F]-FDG PET/CT correlate with the immune landascape in soft-tissue sarcomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5613.
Abstract 6508: Eclipse, an automated CRISPR platform for the large-scale generation of cell models
Authors: Peter Deng, Matthew Rowe, Anna King, Dana Sailor, Antinea Chair, Montse Morell, Andreia G. Sommer, Kevin Holden
Journal: Cancer Research (2023)

Abstract Major advances in gene editing using CRISPR have improved accessibility for the creation of disease relevant in vitro models, allowing researchers to readily interrogate oncogenic driver mutations and elucidate novel targets to overcome challenges within cancer research such as drug resistance. Despite this, the rapid generation of disease relevant cell lines at the scale needed for successful and efficient therapeutic development remains challenging in part due to the sheer number of potential oncogenic driver mutations and cancer targets along with using traditional manual approaches. Specific challenges include: the efficient generation of gene knockouts and corresponding loss of protein; efficient knock-in of gene tags and single nucleotide variants; and controlling the zygosity of these genetic outcomes. To address these limitations, we describe the use of our automated, high throughput CRISPR editing platform, ECLIPSE, for the rapid generation of cell models such as immortalized cells and induced pluripotent stem cells. We leveraged our chemically modified synthetic sgRNAs, optimized nucleofection methods, and automated pipelines for the generation of CRISPR-edited cells at various scales to address the needs of researchers. This scale ranges from individual edited cell clones for drug target validation to the generation of hundreds of knockout cell pools in a ready-to-assay arrayed format for gene target identification in drug screening. The utilization of automated systems such as the ECLIPSE platform are critical catalysts for the rapid generation of engineered cell lines at relevant scales to address the challenges of cancer research. Citation Format: Peter Deng, Matthew Rowe, Anna King, Dana Sailor, Antinea Chair, Montse Morell, Andreia G. Sommer, Kevin Holden. Eclipse, an automated CRISPR platform for the large-scale generation of cell models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6508.
Abstract 1227: Esophageal cancer shows spontaneous plasticity between epithelial and mesenchymal status
Authors: Kenji Tsuchihashi, Yuki Hirata, Juntaro Yamasaki, Kentaro Suina, Kenro Tanoue, Toshifumi Yae, Kenta Masuda, Eishi Baba, Koichi Akashi, Yuko Kitagawa, Hideyuki Saya, Osamu Nagano
Journal: Cancer Research (2023)

Abstract Epithelial-mesenchymal transition (EMT) is one of essential processes in cancer progression. Plasticity between epithelial and mesenchymal status is referred as epithelial-mesenchymal plasticity (EMP). The significance of spontaneous change of EMP is under investigation in the field of EMT. To date, spontaneous EMP is reported in breast and prostate cancer, which leads to the acquisition of stem-cell properties and chemoresistance. On the other hand, the presence of spontaneous EMP is still not examined in other cancer including esophageal cancer. In the present study, we tackled the question of whether esophageal cancer have the potency of spontaneous EMP. We screened eleven esophageal squamous cancer cell (ESCC) cell lines with CD44 isoform expression, which is known to reflect epithelial and mesenchymal status. Interestingly, KYSE520 was found to comprise heterogenous populations consisting of CD44v+ and CD44v- subpopulations. CD44v+ and CD44v- cells showed the expression of epithelial and mesenchymal markers, respectively. Single-cell sorting of CD44v+ and CD44v- cells revealed both cells gave rise to cell populations consisting of CD44v+ and CD44v- cells, indicating CD44v+ epithelial-like and CD44v- mesenchymal-like cells can generate counterparts, respectively. This EMP was maintained in next generation. Further, we found the generation of counterparts between CD44v+ and CD44v- cells in vivo. Epithelial splicing regulatory protein 1 (ESRP1) is reported as the regulator of CD44 mRNA splicing. The role of ESRP1 in EMP is not well understood in esophageal cancer. The inhibition of ESRP1 shifted CD44v+ to CD44v- cells in KYSE520. However, the expression of epithelial-mesenchymal transition (EMT)-related markers or transcriptional factors were almost not affected, suggesting ESRP1 functions downstream of EMP. Our results firstly revealed the presence of spontaneous EMP in esophageal cancer and give a new insight in the field of EMT. Citation Format: Kenji Tsuchihashi, Yuki Hirata, Juntaro Yamasaki, Kentaro Suina, Kenro Tanoue, Toshifumi Yae, Kenta Masuda, Eishi Baba, Koichi Akashi, Yuko Kitagawa, Hideyuki Saya, Osamu Nagano. Esophageal cancer shows spontaneous plasticity between epithelial and mesenchymal status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1227.
Abstract 2529: Necrosome translocates to lysosome to induce lysosome membrane permeabilization and subsequent necroptotic cell death
Authors: Jamila Mammadova, Rojin Fatirkhorani, Shuzhen Liu, Ken Chen, Zhigao Wang
Journal: Cancer Research (2023)

Abstract Introduction: Necroptosis is a cellular process known to be downregulated by cancer cells, and its molecular steps have been described in the literature. Mixed-lineage kinase domain like (MLKL) protein is the most terminal effector of necroptosis. Necroptosis has previously been shown to be activated by the formation of necrosome complex consisting of receptor interacting serine/threonine kinase 1 (RIPK1)-RIPK3-MLKL. MLKL is activated by RIPK3 via phosphorylation, forming phospho-MLKL (P-MLKL), leading to MLKL polymerization and cell necroptosis via lysosome membrane permeabilization (LMP) and plasma membrane rupture. We propose that the necrosome locates onto the lysosome, leading to MLKL-activation induced LMP before cell membrane rupture. Objectives: Our objective is to show that necrosome formation occurs on lysosomal membrane, which then leads to the formation of P-MLKL, and, subsequently, necroptosis via LMP and plasma membrane rupture. Methods: HT-29 cells with hemagglutinin (HA) tagged lysosomal transmembrane protein were induced to undergo necroptosis with the treatment of TNF (T), Smac-mimetic (S) and Z-VAD-FMK (Z) (abbreviated as T/S/Z). Lysosomes were extracted first by cell rupture via homogenization and then immunoprecipitation using anti-HA magnetic beads. Results: Our results suggest that LMP precedes plasma membrane permeability and that MLKL activation takes place on lysosomal membrane. Western blotting demonstrated that lysosomal cathepsin proteases, including CTSA, CTSB, CTSC, CTSD and CTSK, were released into cytosol during necroptosis, confirming lysosomal damage. Furthermore, P-RIPK1, P-RIPK3, P-MLKL and MLKL tetramer were found to be specifically associated with purified lysosomes upon necroptosis induction. Conclusions: MLKL activation on lysosomal membrane and LMP constitute an important step of necroptosis. [J.M. and R.F. contributed equally to this work.] Citation Format: Jamila Mammadova, Rojin Fatirkhorani, Shuzhen Liu, Ken Chen, Zhigao Wang. Necrosome translocates to lysosome to induce lysosome membrane permeabilization and subsequent necroptotic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2529.
Abstract 2826: Electromagnetic fields and hyperthermia induce lysosomal permeabilization and death in different cancer cell models: <i>in vitro</i> and <i>in vivo</i> studies
Authors: Elena Obrador, Ali Jihad-Jebbar, Rosario Salvador-Palmer, Rafael López-Blanch, María Oriol-Caballo, María Paz Moreno-Murciano, Enrique Navarro, Rosa Cibrián, Jose M. Estrela
Journal: Cancer Research (2023)

Abstract Introduction: Non-ionizing radiations (NIR), e.g. tumor-treating fields, high intensity focused ultrasounds (HIFU) or high frequency microwaves, have potential applications in Oncotherapy. Nevertheless, as today, their efficacy is limited. We investigated whether externally applied magnetic fields and non-ablative hyperthermia affect cancer cell viability and growth. Methods: Under in vitro conditions, human A2058 melanoma, AsPC1 pancreas carcinoma, and MDA-MB-231 breast carcinoma cells were treated with electromagnetic fields (EMFs, using solenoids) and/or hyperthermia (HT, using a thermostated water bath). The effect of both energies was also studied in combination with standard chemotherapy and targeted therapy. An experimental system combining EMFs and HIFU-induced HT was developed and tested in vivo. Results: EMFs (25 μT, 4h) or HT (52ºC, 40 min) quite moderately affect cancer cell viability. However, their combination decreased viability to approx. 16%, 50%, and 21% of controls values in A2058, AsPC1, and MDA-MB-231 cells, respectively). Increased lysosomal permeability, release of cathepsins into the cytosol and activation of the mitochondria-dependent cell death are the underlying mechanisms. Cancer cells were completely eliminated combining EMFs, HT and standard chemotherapy or EMFs, HT and anti-Hsp70-targeted therapy. In vivo experiments, using pancreatic cancer xenografts growing in nude mice, show that combination of EMFs, HIFU-induced HT and gemcitabine induces a drastic cancer regression (to approx. 3-4% of control values). Conclusion: Non-invasive NIR (EMFs and HIFU-induced HT) can complement current Oncotherapies. This strategy, associated to current chemotherapy or anti-Hsp70-targeted therapy, may facilitate the elimination of tumors that can be previously located using standard imaging techniques (CT scan and NMR). These results may help to overcome the limitations in the use of different NIR in Oncotherapy. Citation Format: Elena Obrador, Ali Jihad-Jebbar, Rosario Salvador-Palmer, Rafael López-Blanch, María Oriol-Caballo, María Paz Moreno-Murciano, Enrique Navarro, Rosa Cibrián, Jose M. Estrela. Electromagnetic fields and hyperthermia induce lysosomal permeabilization and death in different cancer cell models: in vitro and in vivo studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2826.